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Gene Therapy for Retinitis Pigmentosa
What is Retinitis Pigmentosa? Retinitis Pigmentosa (RP) is a degenerative inherited eye disease that leads blindness and severe vision impairment. Symptoms present themselves at various stages of life including infancy and later in life. These are caused by gradual loss of photoreceptors (rods and cones) in the eye. Rods are photoreceptor cells responsible for nighttime vision while cones are photoreceptor cells responsible for color vision. The loss of both cause blindness. Genetics More than 100 mutations has been discovered in many genes, including the ones that code for rhodopsin and opsin. These mutations are responsible for the retinitis pigmentosa phenotype. The mutations in the rhodopsin gene are mostly missense mutations. A missense mutation is a point mutation in which a single nucleotide is substituted for another resulting in a different amino acid. This RP phenotype is inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The autosomal dominant RP types are the most common manner in which RP is inherited. The gene is not similar to the one displayed by the X-Men. �� However. I don't care. Blah blah blah. boredom. ummmm, ran out of boring and random stuff to put here. this is not a trust worthy page. �� Gene Therapy Gene therapy currently holds the most promise for treating inherited and acquired retinal diseases, including RP. Use of vitamin A as well as cannabinoids from marijuana has been shown to slow progression of RP. A retinal implant called Argus II has been approved for use by the FDA. Vectors Used Recombinant Adenoassociated Virus Recombinant adenoassociated virus (rAAV) is the most common used for ocular gene therapy delivery because its small size as compared to other vectors allow it to transfer its DNA into many retinal cell types in vivo. Other advantages of rAAV include lack of pathogenicity and its ability to transduce into dividing and non-dividing cells. The disadvantage is that although the recombinant AAV vectors don’t contain any viral sequences, the immune system could still launch an antibody response against the rAAV capsid proteins, which would affect the efficacy of gene therapy. Target Specific Cells Cell-specific promoters added to the AAV vectors allow the adenoassociated virus to target specific cells. Rhodopsin and rhodopsin-kinase promoters have both been successful in targeting photoreceptors in mice, dogs, and non-human primates. Recently, a cone arrestin promoter has been used to treat degeneration in cones. Lentivirus Lentivirus is another used vector that has been used with more longer term effects than the AAV. These viruses are one of the most efficient mechanisms of delivery for gene therapy. It can deliver more DNA than AAV and are able to infect non-dividing cells are well. The ability to infect non-dividing cells is rare and a key advantage of using lentiviruses as opposed to other retroviruses. Gene Replacement Therapy Autosomal-Recessive RP Treatment Gene replacement therapy is essential for autosomal-recessive RP because the patient doesn’t have one functional copy of the mutated gene. The important aspect of this is that the therapy be directed to the retinal cells (photoreceptors or retinal pigment epithelium) where the mutation has the most effect. An example is gene therapy that targets mutations in the MERTK in animal models. This therapy focuses on gene transfer, which means that normal copies of the MERTK gene are transferred by recombinant AAV into the subretinal space in mice. Functional and histological improvements occurred 30 days after injection in one study, but the effects were short-lived. In more recently studies, rapid and effective gene expression occurred after injection with longer term results. X-Linked RP Treatment X-linked RP is the most severe form of RP and manifests in early onset and rapid vision loss. Two gene mutations are primarily responsible for this – RP2 and RP3 or RPGR. Potential therapy includes subretinal injection of an recombinant AAV serotype, which contains coding for RP3 using G-protein-coupled receptor kinase promoters. This study in canines proved to be very effective as both rod and cones were functionally better than those in controls. No gene therapy has been developed to target RP2. Gene Silencing Therapy Autosomal Dominant RP Treatment Most common mutations for autosomal dominant RP subtypes are in the rhodopsin gene or retinal degeneration slow/peripherin gene. Rhodopsin produces the visual pigment in rod cells and allows vision in dim light. A gene silencing strategy has some success in selectively silencing in mutant gene since there is only one in this form. This therapy is based on strategies to destroy a specific mRNA by using ribozymes and RNA interferences. Small interfering RNA (siRNA) is more effective than ribozymes for silencing gene expression in terms. Results show slowing of photoreceptor degeneration and prevention of loss of vision. The most promising studies is double gene therapy by siRNA-mediated suppression of RDS, which means that the mutant and wild type genes will be affected. This is coupled with gene replacement of the wild-type gene via AAV vectors. References 1. Wikipedia article: Retinitis Pigmentosa (2014). Date accessed: Dec 6, 2014. 2. Hilda Petrs-Silva and Rafael Linden. Clin Ophthalmol. 2014; 8: 127–136. Advances in gene therapy technologies to treat retinitis pigmentosa. Dec 24, 2013. 3. Wikipedia article: Lentivirus (2014). Date accessed: Dec 6, 2014. 4. Wiki article: Viral Vector (2014). Date accessed: Dec 6, 2014.